Obesity among adults and children is an increasing problem due generally to increases in caloric intake coupled with declines in exercise levels. Morbid obesity among the same population is also increasing as these habitual tendencies are coupled with physiologic conditions of certain individuals predisposed to obesity that may not fully understood in a given case. The primary treatment has always involved behavorial change involving dietary restraints to reduce caloric intake coupled with aerobic and anaerobic exercise routines or physical therapy regimens to increase caloric expenditure, resulting in a net caloric reduction. Diet and exercise plans fail since most individuals do not have the discipline to adhere to such rigorous discipline. Consequently, the marketplace is flooded with resurrected or new dietary supplements and ethical (or prescription) and patent (or nonprescription) drugs or other ingestible preparations promoted as capable of suppressing appetite or inducing satiety (i.e., the satisfied feeling of being full after eating) or of “burning” fat.
More radical surgical approaches are also commonly employed particularly liposuction (suction lipectomy) for removing adipose tissue from obese patients. Liposuction also enjoys wide application for cosmetic reshaping of the anatomy, particularly the abdomen, hips, thighs and buttocks of non-obese persons. In advanced or extreme cases, treatment of obesity has included more radical techniques such stapling or re-sectioning of the stomach, or wiring the jaws shut.
In general, these and other prior art techniques for treating compulsive overeating/obesity have tended to produce only a temporary effect. The individual usually becomes discouraged and/or depressed in the course of the less radical therapies primarily focused on behavioral change after the initial rate of weight loss plateaus and further weight loss becomes harder to achieve. The individual then typically reverts to the previous behavior of compulsive overeating and/or indolence. And individuals undergoing liposuction and jaw wiring may enjoy their lower weight and bulk for a time, but eventually typically regain the excised or lost weight and volume. The surgical resection of the stomach works well for some individuals, but others experience serious unpleasant side effects that, together with the risk, recuperation pain, and expense of such major surgery, discourage its widespread adoption.
Many other therapies have been proposed, including electrical stimulation of the stomach and/or gut to block stomach emptying and prolong a feeling of satiety as disclosed in U.S. Pat. Nos. 5,423,872 and 5,690,691. It is believed that a satiety center in the brain develops the sensation of satiety in a complicated manner believed in part to be due to increased firing of afferent vagal fibers of the vagal nerves extending between the stomach and brain when the stomach is filled. Thus, it has been proposed to electrically stimulate the stomach or the vagus nerves, as set forth in U.S. Pat. Nos. 5,263,480 and 5,188,104, at a rate mimicking the observed increase to mediate afferent information from the stomach to the satiety centers. Unfortunately, it is not a simple procedure to implant the stomach wall or vagal nerve electrodes, or to do so in an effective place to accomplish the goal of inducing the satiety sensation when the stomach is not actually full. And, the vagal nerves are involved in the regulation of the function of many body organs, including the heart, and stimulation of vagal nerves for any given purpose can have unintended consequences.
Although the blame for weight gain due to the inability to reduce caloric intake and increase caloric expenditure in exercise was historically laid upon the sins of gluttony and sloth, a great deal of evidence has been gleaned from observation and controlled experiments that supports the theory that the body tends to seek and to maintain a body weight in a regulatory manner. Experiments conducted in a wide body of medical research have shown that the body works to regain its previous weight after weight loss due to reduced net caloric input, particularly involving shrinkage of adipose tissue, is achieved by more efficiently rebuilding the adipose tissue, even if net caloric input remains reduced from where it was at the outset. Genetically, the body is predisposed to accumulate adipose stores to forestall famine employing an efficient regulatory system that matches caloric intake to caloric expenditure. Thus, it appears that once the body achieves a historic volume of adipose tissue, the regulatory system works to maintain that historic volume of adipose tissue that it has worked to achieve despite attempts to reduce it through reduced net caloric intake.
It has been postulated that the weight maintaining mechanism is also influenced by insulin that circulates in CSF in the interstitial spaces of the brain which binds with insulin receptors in brain regions known to be involved in the regulation of food intake and body weight. However, it is unclear how insulin enters the CNS, because its molecular size would seemingly prevent insulin in the blood stream from passing through the blood-brain barrier (BBB). It is postulated that the CNS itself may have a limited capacity to synthesize and release insulin locally or that a specialized transport process exists to transport plasma insulin across the BBB. See, for example, the article by M. W. Schwartz et al., “Insulin in the Brain: A Hormonal Regulator of Energy Balance”, Endocrine Reviews Monographs, August 1992, vol. 13, no. 3, pp. 387–414.
The weight control effects of delivering insulin directly into the brain of the CSF circulating in the brain have been reported in further articles including: (1) M. Chavez et al., “Intraventricular Insulin and the Level of Maintained Body Weight in Rats”, Behavorial Neuroscience, 1995, Vol. 109, No. 3, pp. 528–531; (2) G. L. Florant et al., “Intraventricular Insulin Reduces Food Intake and Body Weight of Marmots During the Sumer Feeding Period”, Physiology & Behavior, 1991, Vol. 49, pp. 335–338; (3) A. J. Sipols et al., “Effect of Intracerebroventricular Insulin Infusion on Diabetic Hyperphagia and Hypothalamic Neuropeptide Gene Expression”, Diabetes, February 1995, Vol. 44, pp. 147–151; and (4) S. C. Woods et al., “Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons”, Nature, Nov. 29, 1979, Vol. 282, pp. 503–505. The authors report the results of direct infusion of predetermined dosages of insulin at predetermined daily rates into the CSF in the intracerebroventricular spaces around the brain ventricles of rats, marmots or baboons
Theoretical explanations of the interactions of a number of drugs or chemicals with receptors in the brain are presented in U.S. Pat. No. 5,290,808. The complex influence of central neurochemical activity on the expression of appetite involves numerous interactions between different loci and different receptors that result in shifts in the magnitude, direction and quality of eating behavior. The '808 patent further states that a great deal of data has been accumulated from the direct application of drugs to specific sites of the brain or the indirect application of drugs to the brain via the CSF which is supported by the above literature citations. Most agents suppress intake but a significant number stimulate eating, sometimes in a dramatic fashion. The most frequently demonstrated action is the stimulation of feeding following activation of 2-adrenoceptors in the paraventricular nucleus (PVN). It is also known that spontaneous feeding is associated with endogenous release of noradrenaline in the PVN, and with an increase in PVN 2-adrenoceptor density. In turn, it appears that the PVN is a site for the long-established anorexic action of 5-HT receptor agonists. The PVN also contains glucosensitive neurons and therefore may be a point of interaction for neurotransmitter activity and metabolic states reflecting energy regulation. Circulating corticosteroids have been demonstrated to influence 2-adrenoceptor sensitivity, and it has been argued that noradrenaline and 5-HT act antagonistically to influence the release of CRF. Since the PVN is also a potent anorectic drug binding site, neurochemical activity in this area may serve to integrate behavioral, metabolic and neuroendocrine responses. In more lateral areas of the hypothalamus (perifornical zone) feeding is suppressed by micro-injection of agents that activate dopamine D2 receptors or B2-adrenoreceptors. Noradrenaline, 5-HT and dopamine consequently produce quantitative shifts in feeding from closely related sites in the hypothalamus.
The '808 patent further states that potent feeding responses can also be obtained by micro-injection of peptides to the brain. Many peptides such as insulin, CCK, calcitonin, bombesin, neurotensin, THRH, somatostatin, VIP, CRF and glucagon suppress feeding after cerebroventricular administration. A smaller number of peptides, including B-endorphin, dynorphin, neuropeptide Y, peptide YY and galanin, increase food intake.
The '808 patent does not propose directly injecting such appetite influencing drugs into the brain or CSF, but instead discloses particular drug dosage forms for oral administration.
An implantable infusion pump (IIP) comprising an implantable pump and catheter is disclosed in commonly assigned U.S. Pat. Nos. 5,643,207 and 5,782,798 for dispensing pancreatic polypeptide blockers and other drugs that decrease sensations of hunger and increase satiety into particular sites in the brain through a distal catheter segment that is implanted through the skull and extends to the specific sites. The delivery of other appetite influencing drugs directly into the brain for increasing appetite to treat anorexia is also proposed in the '207 patent. The drug that is dispensed from the infusion pump coupled to the catheter through the catheter lumen and into the brain is expected to induce or increase the feeling of satiety to treat obesity by reducing caloric intake or to increase feelings of hunger to treat anorexia by increasing caloric intake. The system of the '798 patent can also be employed to apply electrical stimulation to the brain through catheter borne electrodes and conductors to increase feelings of satiety to treat obesity or to decrease feelings of satiety to treat anorexia presumably either with of without delivery of the identified drugs. While these treatments have merit, the implantation of a catheter and stimulation electrodes through a skull entry into the brain is a significant surgical procedure. Also, it is necessary to form a complex catheter and lead preformed with or capable of making a 90° turn at the skull entrance so that the more proximal catheter segment can be tunneled under the scalp, down the neck and to the chest region, where the combined neurostimulator and IIP are implanted.
Obesity is often associated with diabetes, and diabetics inject insulin into their bodies to control its symptoms. In recent years, IIPs have been developed to deliver insulin for patients with diabetes. External pumps deliver insulin into subcutaneous tissue via a percutaneous needle connected to a battery powered external pump worn and controlled by the patient. Implantable battery powered IIPs have also been used to deliver insulin to the peritoneal cavity.
Therapeutic administration of pain suppression or therapeutic drugs into the intraspinal space, that is to either the epidural space or to the intrathecal space, is known. The spinal cord is surrounded by three meningeal sheaths that are continuous with those which encapsulate the brain within the enclosure by the vertebral canal for the spinal cord by the bones of the vertebrae. The outermost of these three meningeal sheaths is the dura matter, a dense, fibrous membrane which anteriorally is separated from the periosteum of the vertebral by the epidural space. Posterior to the dura matter is the subdural space. The subdural space surrounds the second of the three meningeal sheaths, the arachnoid membrane, which surround the spinal cord. The arachnoid membrane is separated from the third meningeal sheath, the pia mater, by the subarachnoid or intrathecal space. The subarachnoid space is filled with CSF. Underlying the pia mater is the spinal cord. Thus the progression proceeding inwards or in posterior manner from the vertebra is the epidural space, dura mater, subdural space, arachnoid membrane, intrathecal space, pia matter and spinal cord.
Administration of a drug directly to the intrathecal space can be by either spinal tap injection or by catheterization. Intrathecal drug administration can avoid the inactivation of some drugs when taken orally as well and the systemic effects of oral or intravenous administration. Additionally, intrathecal administration permits use of an effective dose that is only a fraction of the effective dose required by oral or parenteral administration. Furthermore, the intrathecal space is generally wide enough to accommodate a small catheter, thereby enabling chronic drug delivery systems. Thus, it is known to treat spasticity by intrathecal administration of baclofen. Additionally, it is known to combine intrathecal administration of baclofen with intramuscular injections of botulinum toxin for the adjunct effect of intramuscular botulinum for reduced muscle spasticity. Furthermore, it is known to treat pain by intraspinal administration of the opioids morphine and fentanyl.
The current method for intrathecal treatment of chronic pain is by use of an intrathecal IIP, such as the SynchroMed® Infusion System, a programmable, implanted pump available from Medtronic, Inc., of Minneapolis, Minn. A pump is required because the antinociceptive or antispasmodic drugs in current use have a short duration of activity and must therefore be frequently re-administered, which re-administration is not practically carried out by daily spinal tap injections. The pump is surgically placed under the skin of the patient's abdomen. One end of a catheter is connected to the pump, and the other end of the catheter is threaded into a CSF filled subarachnoid or intrathecal space in the patient's spinal cord. The implanted pump can be programmed for continuous or intermittent infusion of the drug through the intrathecally located catheter.